When creating a file system ( mkfs ...) the file system reserves 5% of the space for its own use because, according to man tune2fs:

Reserving some number of filesystem
blocks for use by privileged processes
is done to avoid filesystem
fragmentation, and to allow system
daemons, such as syslogd(8), to
continue to function correctly after
non-privileged processes are prevented
from writing to the filesystem.

But with large drives 5% is quite a lot of space.

I have 4x1.5 TB drives for data storage (the OS runs on a separate disk), so the default setting would reserve 300 GB, which is an order of magnitude more than the the entire OS drive.

The reserved space can be tweaked, but what is a reasonable size for a data disk? Can I set it to zero, or could that lead to issues with fragmentation?

If you set the reserved block count to
zero, it won't affect performance much
except if you run for long periods of
time (with lots of file creates and
deletes) while the filesystem is
almost full (i.e., say above 95%), at
which point you'll be subject to
fragmentation problems. Ext4's
multi-block allocator is much more
fragmentation resistant, because it
tries much harder to find contiguous
blocks, so even if you don't enable
the other ext4 features, you'll see
better results simply mounting an ext3
filesystem using ext4 before the
filesystem gets completely full.

If you are just using the filesystem
for long-term archive, where files
aren't changing very often (i.e., a
huge mp3 or video store), it obviously
won't matter.